Animal feed and process

ABSTRACT

An animal feed for increasing meat, milk, or egg production comprising a compound of the group consisting of a compound of the formula: OR OXYGEN; WHEREIN R1 is hydrogen or alkyl, defined as above; wherein R2, R3, R4, and R5 are selected from the group consisting of hydrogen, alkyl defined as above, halogen, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, and dialkylamino, in which the carbon chain moiety is of one to three carbon atoms, inclusive, and in which the 5 to 6 nitrogen carbon linkage is selected from the group consisting of double bonds and single bonds, with the proviso that the linkage is always a double bond whenever R&#39;&#39;&#39;&#39; is oxygen; and the pharnacologically acceptable acid addition salts in combination with the nutrient feed.   WHEREIN R&#39;&#39; and R&#39;&#39;&#39;&#39; are hydrogen, or alkyl of one to three carbon atoms, inclusive, or together     ARE PYRROLIDINO, PIPERIDINO, HEXAMETHYLENEIMINO, OR MORPHOLINO; R&#39;&#39;&#39;&#39;&#39;&#39; is   D R A W I N G

United States Patent Collins 11 May 21, 1974 [54 ANIMAL FEED AND PROCESS [75] Inventor: Robert J. Collins, Portage, Mich.

[731 Assignee: The Upjohn Company, Kalamazoo,

Mich.

[221 Filed: Aug. 9, 1971 [211 Appl. No.: 170,317

[52] US. Cl 424/269, 424/248, 424/267 [51] InL-Cl A6lk 27/00 [58] Field of Search 424/269, 248, 267

[56] References Cited FOREIGN PATENTS OR APPLICATIONS 6,916,543 5/1970 Netherlands ..424/269 Primary Examiner-Albert T. Meyers Assistant Examiner-Frederick E. Waddell Attorney, Agent, or Firm-John J. Killinger; Roman Saliwanchik x [57] ABSTRACT An animal feed for increasing meat, milk, or egg production comprising a compound of the group consisting of a compound of the formula:

Formula I wherein R and R" are hydrogen, or alkyl of one to three carbon atoms, inclusive, or together are pyrrolidino, piperidino, hexamethyleneimino, or

morpholino; R' is able acid addition salts in combination with the nutrient feed.

6 Claims, N0 Drawings l ANIMAL FEED AND PROCESS U.S. Pat. No. 3,759,945, which discloses compounds of the Formula l and methods for their preparation.

BRIEF SUMMARY or THE INVENTION Broadly the present invention encompasses a nutritionally adequate animal feed having dispersed therein a compound of the Formula I in sufficient concentration to provide increasing productivity and feed effi-- ciencies in healthy meat-producing, milk-producing or egg-laying animals. The invention also includes the process of feeding the composition to meat-producing, milk-producing or egg-laying animals.

DETAILED DESCRIPTION It has been found in recent years that meat-producing animals will gain more weight and gain it faster when various classes of compounds such as vitamins, miner als, estrogens, antibiotics, and tranquilizers are added to the diet. Although the presently available compounds are useful, new materials are still being sought that would produce weight gains more rapidly, to a greater extent, more efficiently with respect to feed intake at a lower cost and without undersirable side effects. i

It is now possible by use of the present invention to obtain unexpected results in the feeding of meatproducing, milk-producing, or cgg-laying animals; that I is to say, an increased rate of weight gain, an increased amount of weight gain, an increase in milk production, or increased rate of egg laying, as well as increased feed efficiency, can be obtained by the addition of minute quantities of a compound of the Formula 1 to the animals usual nutrient feed.

Compounds of the Formula 1 can be prepared by methods disclosed in United States application Ser. No. 138,287, filed Apr. 28, 1971, now U.S. Pat. No. 3,759,945.

Unless otherwise specified, all percentages are given on a weight-to-weight basis. The pound (1b.) weights given are avoirdupois units.

Feeding of the compositions of the present invention can commence for birds shortly after hatching and in the case of mammals, during the creep-feeding period of suckling animals'when they are starting on solid food and, of course, after weaning. Feeding of the compositions is continued throughout the growing period, lactation period, or egg-laying period.

The total concentration of the compound of the Formula l in the feed composition is determined with regard to the species of animal, age, weight, and average amount of feed consumed daily. Preferably the compound of the Formula 1 is employed in the finished feed that will supply the animal with a daily intake of from about 0.3 mg. to about 500 mg. per head per day.

The following table illustrates the range of compound of Formula 1 in milligrams daily dose per head per day for representative animals.

Range Daily Preferred Animal Dose/Head. mg. Daily Dose, mg.

Swine (birth to 8 weeks) 0.25-25 1.4 Swine (40 to 200 lbs.) l.45l4,5 30 Chickens (growing -8 weeks) 0.03-3.0 0.2 Hens (laying) 0.06-60 0.3 Turkeys (growing 0-24 weeks) 0.2l0 0.5 Beef Cattle (fattening) 50-500 28 Calves (0-12 weeks) 0.6-60 30 Dairy Cattle (lactation) 5.0-()0 28 Lambs (fattening) 0.3838 2.0

' a premix composition prepared by mixing 1.4 gm. of

in a fluid vehicle such as corn oil, cottonseed oil, molas ses, distillers solubles and the like to prepare a fluid premix. Alternatively, a solid premix can be prepared by mixing a compound of the Formula 1 with an edible solid .diluent such as sucrose, lactose, starch, corn meal, flour, calcium carbonate, soybean meal and the like.

EXAMPLE 1 A diet for fattening lambs is prepared from the following types and amounts of ingredients:

Ground car com 82.05% Alfalfa meal I().()% Soybean oil meal 44 7.0% Ground limestone 0.371 Salt 0.69! Trace mineral mixture 0.05%

Contains the following percent of minerals: Mn, l2, Co, 0.08; Fe, 5.0; Cu, 0,4: I, 0.24; Zl'lv 0.7. l

The above feed to be mixed, pelleted and offered to fattening lambs free-choice in conjunction with hay.

To 999 parts of the preceding feed is added 1 part of 8-chloro-N,N-dimethyl-6-phenyl 4l-l-s-triazolo[4,3- a][ l,4]-benzodiazepine-l-acetamide with sufficient corn meal to make one pound.

The feeding composition so prepared supplies 1.4 mg. of 8-chloro-N,N-dimethyl-6-phenyl-4H-striazolo[4,3-a]-[ 1,4]benzodiazepinel -acetamide per pound or 3.1 parts per million.

t The foregoing composition is-usefully fed to lambs for increased rate of weight gain and improved utilization of feed.

EXAMPLE 2 A chicken feed for broilers is prepared from the following types and amounts of ingredients:

Consisting of 16.0 gm. Vitamin A supplcmenll luni1s/nig.);3.o gm. Vitamin D supplement (15.000 units/gm); 7.1 gm. riboflavin supplement (1 gm. riboflavin per ounce); 500 mg. niacin.

EXAMPLE 3 A fattening feed for 800 pound yearling cattle is prepared from the following types and amounts of ingredients:

Ground car corn 89.75%

Soybean oil meal. 44% 90% Ground limestone 0.7% Salt 0.5% Trace mineral mixture 005% Contains the following percent of minerals: Mn. 12; Co. 0.08; Fe. 5.0; Cu. 0.4; l. 0.24: '/.n. 0.7.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 3.0 gm. of 8-chloro-N,N-dimethyl-6-phenyl-4H-s-triazolo[4,3-

a][ 1,4]-benzodiazepine-l-acetamide with sufficient wheat flour to make 1 pound.

The feeding composition so prepared supplies 3.0 mg. of S-chloro-N.N-dimethyl-6-phenyl-4H-striazo|o[4,3-a]-l 1,4]benzodiazepine-l-acetamide per pound, or about 6.6 parts per million.

Cattle are to receive the foregoing feed ad libitum together with lb. of hay per head per day and when so fed have an increased rate of weight gain and improved utilization of feed.

EXAMPLE 4 A swine diet for growing hogs of 40 to 100 pounds body weight is prepared from the following types and amounts of ingredients:

Corn. ground 78.15% Soybean oil meal. 44% 17.0% Meat and bone scraps. 50% 30% Oyster shell flour 0.4% Bone meal 0.5% Salt 0.5% Trace mineral mixture 005% Zinc oxide 0.01% Vitamin A and D supplement 0.25% B Vitamin supplement 0.05%

-Continued Vitamin B supplement" 0.09%

Contains the following of minerals; Mn. 12; Co. 0.08; Fe. 5.0; Cu. 0.4; 1.0.24; Zn. 0.7.

Contains 300 USP units D;,/(im. and 1500 l.U.A./(im.

Contains per 1b.: Riboflavin. 2000 mg; calcium pamothcnaie 4000 mg; niac 9000 mg; and choline chloride 10,000 mg.

"Contains 6 mg. Vitamin 13. per 1h.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 1.5 gm. of 8-chloro-N,N-dimethyl-6-phenyl-4H-s-triazolo[4.3-

a][ l,4l-benzodiazepine-l-acetamide with sufficient ground limestone to make one pound.

The feeding composition so prepared supplies 1.5 mg. of 8-chloro-N,N-dimethyl-6-phenyl-4H-striazolo[4,3-a]-[ 1,4]benz0diazepine- 1 -acetamide per pound, or about 3.3 parts per million.

The foregoing composition is usefully fed to hogs for increased rate of weight gain and improved utilization of feed.

EXAMPLE 5 Following the procedure of the preceding examples 1 to 4, inclusive, animal feeds are similarly prepared substituting equimolar amounts of:

N,N-dimethyl-8-chloro-6-(o-chlorophenyl)-4H-striazolo[4.3-a][ l,4]benzodiazepine-l-acetamide;

N,N-dimethyl-8-chloro-6-(2,6-dichlorophenyl)-4H- s-triazolo[4,3-a][ 1 ,4lbenzodiazepine- 1 -acetamide;

N,N-dimethyl-8-chloro-6-(2,6-diflu0rophenyl)-4H-striazolo[4,3-a][ 1,4]benzodiazepine- 1 -acetamide;

N,N-tetramethylene-4-methyl-8-nitro-6-(mbromophenyl )-4H-s-triazolo[4,3-a][ 1 ,4]benzodiazepinel-acetamide;

N,N-pentamethylene-7-trifluoromethyl-6-(ochlorophenyl)-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine-l-acetamide;

N,N-hexamethylene-10-isopropyl-6-(pmethylthiophenyl )-4H-s-triazolo[4,3- a][ 1 ,4]benzodiazepine- [-acetamide;

4-[ [9-dipropylamino-8-ethylsulfonyl-6-( pmethoxyphenyl)-4H-s-triazolo[4,3- a][ l .4]benzodia-zepinel -yl]-acetyl ]morpholine;

N,N-dipropyl-9-ethylsulfinyl-6-(m-nitrophenyl)-4H- s-triazolo[4,3-a][ 1,4]benzodiazepinel -acetamide;

7.8-dicyanol0-fluoro-6-( pisopropylsulfonylphenyl )-4H-s-triazolol 4.3- a][ 1,4]benzodiazepinelacetamide;

N,N-dimethyl7-bromo'-8-diethylamino-6-(mcyanophenyl)-4H-s-triazolol4,3-a][ 1,4]benzodiazepinel-acetamide;

N,N-dimethyl-4-propyl-8-bromo-6-(obromophenyl)-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine- 1 -acetamide;

1-[2-(dimethylamino)ethyll-8-chloro-5,6-dihydr0-6- phenyl-4H-s-triazolo[4,3-a][ 1 ,4]benzodiazepine;

1-[2-( dimethylamino )ethyl]-8-chloro-5 ,6-dihydro-6- (o-chlorophenyl)-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine;

1-[2-(dimethylamino)ethyl]-8-chloro-5,6-dihydro-6- (2,6-dichlorophenyl)-4H-s-triazolo[4,3- a][1,4]benzodiazepine;

1-[ 2-(diethylamino)ethyl -8-chloro-5 ,6-dihydro-6- (2.6-difluorophenyl )-4H-s-triazolo[ 4.3- a][ 1,4]benzodiazepine;

l-( 2-morph0linoethyl )-7-(ethylsulfonyl )-6-(ocyanophenyl)-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine;

l-( 2-piperidinoethyl )-4-propyl-6-[m-( methylthio)- phenyl]-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine;

l-[ 2-( hexamethyleneimino)ethyl]- l -fluoro-7- chloro-6-[p-(trifluoromethyl)phenyl]-4H-striazolo[4,3-a][ 1,4]benzodiazepine;

l-( 2-pyrrolidinoethyl )-7 ,9-diethoxy-6-(methoxyphenyl)-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine;

l-[2-(diisopropylamino)ethyl ]-4-ethyl-6-[0- (ethylthio)phenyl]-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine;

l-[2-( diethylamino )ethyl]-4-methyl-7, IO-dichloro- 6-[m-(isopropoxy)phenyl]-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine;

l-[ Z-(diethylamino)ethyl]-9-(dipropylamino)-6-[m- (propylthio)phenyl]-4Hs-triazolo[4,3-

a][ 1,4]benzodiazepine;

l-( 2-morpholinoethyl)-7-(diisopropylamino)-6-[p- (dipropylamino)phenyl]-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine;

l-( Z-piperidinoethyl )-8-chloro-6-( 3,4- dimethylphenyl)-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine;

l-(2-pyrrolidinoethyl)-6-(2-methyl-4- methoxyphenyl)-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine;

l-( 2-pyrrolidinoethyl )-8-methylthio-6-phenyl-4H-striazolo[4,3-a]{ 1,4]benzodiazepine;

l-(2-pyrrolidinoethyl)-8-methoxy-6-phenyl-4l-l-striaZolo[4,3-a][1,4]benzodiazepine for the 8-chloro- N,N-dimethyl-6-phenyl-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine of the examples.

I claim:

l. A process for increasing meat, milk or egg production in a healthy meat-producing, milk-producing or egg-laying animal comprising the feeding thereto .of from about 0.03 to about 500 mg./day of a compound selected from the group consisting of a compound of the formula:

N RI] R [/1 2 N-ii-mo-g wherein R and R are hydrogen, or alkyl of one to three carbon atoms, inclusive, or together R! are pyrrolidino, piperidino, hexamethyleneimino, or morpholino; R' is or oxygen; wherein R is hydrogen or alkyl, defined as above; wherein R R R and R are selected from the group consisting of hydrogen, alkyl defined as above, halogen, nitro, cyano, trifluoromethyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, and dialkylamino, in which the carbon chain moiety is of one to three carbon atoms, inclusive, and in which the 5 to 6 nitrogen carbon linkage is selected from the group consisting of double bonds and single bonds, with the proviso that the linkage is always a double bond whenever R' is oxygen; and a pharmacologically acceptable acid addition salt thereof in combination with the nutrient animal feed.

2. The process of claim l-wherein the member selected is in a concentration of from 250 mg. to 25,000 mg. per pound of nutrient carrier in the form of a premix.

3. The process of claim 1 when the member selected is in the concentration from 500 mg. to 50,000 mg. per ton of feed.

4. The process of claim 1 wherein the compound is 8-chloro-N,N-dimethyl-6-phenyl-4H-s-triazolo-[4,3- a][ 1,4]benzodiazepine- [-acetamide.

5. The process of claim 2 wherein the compound is 8-chl0ro-N,N-dimethyl-6-phenyl-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine- 1 -acetamide.

6. The process of claim 3 wherein the compound is 8-chloro-N,N-dimethyl-6-phenyl-4H-s-triazolo[4,3-

a] 1,4]benzodiazepinel-acetamide. 

2. The process of claim 1 wherein the member selected is in a concentration of from 250 mg. to 25,000 mg. per pound of nutrient carrier in the form of a premix.
 3. The process of claim 1 when the member selected is in the concentration from 500 mg. to 50,000 mg. per ton of feed.
 4. The process of claim 1 wherein the compound is 8-chloro-N,N-dimethyl-6-phenyl-4H-s-triazolo-(4,3-a)(1,4)benzodiazepine-1 -acetamide.
 5. The process of claim 2 wherein the compound is 8-chloro-N,N-dimethyl-6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine-1 -acetamide.
 6. The process of claim 3 wherein the compound is 8-chloro-N,N-dimethyl-6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine-1 -acetamide. 